Medication Summary

The mainstay of drug therapy for bacterial pneumonia is antibiotic treatment. The choice of agent is based on the severity of the patient's illness, host factors (eg, comorbidity, age), and the presumed causative agent. Although intravenous (IV) penicillin G is currently not favored, doses in the range of 20-24 million U/d result in serum levels that exceed minimum inhibitory concentration (MIC) levels of most resistant pneumococci.

Glucocorticoids

The role of glucocorticoids in acute bacterial pneumonia has yet to be clearly elucidated. Classic teaching warns that the use of glucocorticoids in infection may impair the immune response. However, findings demonstrate that local pulmonary inflammation may be reduced with systemic glucocorticoids. In a 2015 meta-analysis of 13 randomized controlled trials evaluating the use of systemic corticosteroids in patients hospitalized for CAP,
[61] it was found with high certainty that systemic corticosteroid steroid treatment reduced the duration of hospitalization by approximately 1 day and had a 5% absolute reduction in risk for mechanical ventilation. The study also found that patients with severe pneumonia who received systemic corticosteroids had an apparent mortality benefit over patients with severe pneumonia who did not receive systemic corticosteroids, which may be related to the higher incidence of acute respiratory distress syndrome and the need for mechanical ventilation in patients with severe pneumonia. However, this evidence was rated moderate as the confidence interval crossed 1 and because of a possible subgroup effect. All patients who received corticosteroids had a higher incidence of hyperglycemia requiring treatment. Thus, in immunocompetent patients hospitalized with severe CAP, systemic corticosteroids should be considered, given the possible mortality benefit of systemic corticosteroid treatment in this subgroup of patients.

Outpatient/inpatient antibiotic administration

Outpatients are typically treated with oral antibiotics. For the most part, parenteral medications are given to patients admitted to the hospital. This rationale does not preclude the clinician from giving an initial intravenous (IV) dose of antibiotics in the emergency department and then sending the patient home on oral agents, if the patient's condition warrants this action. The patient's condition, infection severity, and microorganism susceptibility should determine the proper dose and route of administration.

A rational approach may be to administer an oral extended-spectrum macrolide or amoxicillin and clavulanate (Augmentin) to those with mild, outpatient disease. Oral fluoroquinolone may be substituted if a comorbid illness or allergy to the first-line agents is present or for good dosing compliance. Admitted patients should receive IV therapy, a third-generation cephalosporin alone or with a macrolide. An alternative regimen would be IV fluoroquinolones alone.

Pediatric antimicrobial therapy

All agents discussed in the next sections are for use in persons older than 5 years. In children younger than five years of age, initial treatment of pneumonia includes IV ampicillin or nafcillin plus gentamicin or cefotaxime (for neonates). Ceftriaxone or cefotaxime can be administered as a single agent (for >28 d to 5 y). An alternative regimen includes a penicillinase-resistant penicillin plus an antipseudomonal aminoglycoside.

Outpatient treatment of mild-to-moderate pneumonias in children usually involves agents similar to those used for acute otitis media. Most of the pneumonias in these patients probably have a viral cause. In children who have features suggesting a bacterial etiology (eg, an infiltrate on chest radiograph and/or positive findings at sputum Gram stain), the administration of antibiotics may be good clinical practice. In these cases, many clinicians begin empiric therapy with amoxicillin, but its spectrum of activity is lacking, because children in this group who do not have nonviral pneumonia usually have an infection caused by S pneumoniae and Mycoplasma species.

H influenzae type B has been less common since the introduction of the HIB vaccine. Children younger than two years may still be at risk for H influenzae type B infection, because their immune response is not sufficient, as it is in older children. A typical regimen for outpatient therapy may include a new macrolide agent or a second-generation or third-generation cephalosporin. Cost is a potential drawback for all agents.

Macrolides

The best initial antibiotic choice is thought to be a macrolide. Macrolides provide the best coverage for the most likely organisms in community-acquired bacterial pneumonia (CAP). Macrolides have effective coverage for gram-positive, Legionella, and Mycoplasma organisms. Azithromycin administered intravenously is an alternative to intravenous erythromycin.

Macrolides, as a class, have the potential disadvantage of causing gastrointestinal (GI) upset. Compared with erythromycin, newer agents have fewer GI adverse effects and drug interactions, although all macrolides have the potential for drug interactions similar to those of erythromycin. Newer macrolides offer improved compliance because of reduced dosing frequency, improved action against H influenzae, and coverage of Mycoplasma species (unlike cephalosporins). The main disadvantage is cost.

Macrolides are primarily recommended for the treatment of CAP in patients younger than 60 years of age who are nonsmokers without a comorbid illness. Give special consideration to recommendations for antibiotic use in patients with comorbid illnesses or those with CAP who are older than 60 years of age. Although patients in this group are still susceptible to S pneumoniae, they should receive treatment for broader coverage that includes Haemophilus, Moraxella, and other gram-negative organisms. Therefore, a prudent course of action for empiric outpatient therapy is to include: (1) one of the macrolide agents described previously plus a second- or third-generation cephalosporin or amoxicillin and clavulanate or (2) trimethoprim and sulfamethoxazole (TMP-SMZ) as a single agent.

Patients who have moderate clinical impairment or comorbid illnesses are best treated with parenteral agents and, unless a particular agent is strongly suspected, broad coverage should be afforded. Regimens for this use include a macrolide plus a second- or third-generation cephalosporin, (as single agents) ampicillin and sulbactam (Unasyn), piperacillin and tazobactam (Zosyn), or ticarcillin and clavulanate (Timentin).

Of these agents, cefprozil, cefpodoxime, and cefuroxime seem to have better in vitro activity against S pneumoniae. Second-generation cephalosporins are not effective against Legionella or Mycoplasma species. These drugs are generally well tolerated, but cost may be a factor. Oral second-generation and third-generation cephalosporins offer increased activity against gram-negative agents and may be effective against ampicillin-resistant S pneumoniae.

Intravenous cephalosporins may be combined with a macrolide agent. They broaden the gram-negative coverage, and in the case of third-generation agents, they may be effective against resistant S pneumoniae. In addition, some third-generation agents are effective against Pseudomonas, whereas second-generation agents are not.

Combination drugs

The combination of trimethoprim and sulfamethoxazole (TMP-SMZ) may be used in the patient with pneumonia and a history of chronic obstructive pulmonary disease (COPD) or smoking. It may be also used as a single agent in younger patients in whom a Haemophilus species is the suspected agent.

TMP-SMZ is well tolerated and inexpensive. However, allergic reactions are more often associated with drugs in this class than with other antibiotics. Reactions span the spectrum from simple rash (most likely) to Steven-Johnson syndrome and toxic epidermal necrolysis (rare). Many potential drug interactions are noted.

When a severely ill patient has features of sepsis and/or respiratory failure, and/or when neutropenia is known or suspected, treatment with an intravenous macrolide is combined with an intravenous third-generation cephalosporin and vancomycin. An alternative regimen may include imipenem, meropenem, or piperacillin and tazobactam plus a macrolide and vancomycin. A fulminant course also must raise the suspicion of infection with Legionella or Mycoplasma species, Hantavirus, psittacosis, or Q fever.

Fluoroquinolones, including levofloxacin, moxifloxacin, and gatifloxacin, may also be used. These agents are available in oral and parenteral forms and have convenient dosing regimens, which allow easier conversion to oral therapy that results in good patient compliance. Note that in July 2008, a warning was issued from the US Food and Drug Administration (FDA) regarding the risk of tendonitis and tendon rupture with fluoroquinolone use.
[75]

Next:

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

In otherwise uncomplicated pneumonia, azithromycin is the initial drug of choice, as it covers most of the potential etiologic agents, including Mycoplasma species. Compared with other drugs, this agent also causes less GI upset, and it has the potential for good compliance because of its reduced dosing frequency. Azithromycin has better action against H influenzae compared with erythromycin, but its main disadvantage is cost.

Azithromycin is a macrolide that acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. This agent concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that the concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Aztreonam is a monobactam, not a beta-lactam, antibiotic that inhibits cell wall synthesis during bacterial growth. This agent has activity against gram-negative bacilli but very limited gram-positive activity, and it is not useful for anaerobes. Aztreonam lacks cross-sensitivity with beta-lactam antibiotics; it may be used in patients allergic to penicillins or cephalosporins.

The duration of aztreonam therapy depends on the severity of the infection and is continued for at least 48 hours after the patient is asymptomatic or evidence of bacterial eradication is obtained. Doses smaller than indicated should not be used.

Transient or persistent renal insufficiency may prolong serum levels. After an initial loading dose of 1 or 2 g, reduce the dose by half for an estimated creatinine clearance (CrCl) rate of 10-30 mL/min/1.73 m2. When only serum creatinine concentration is available, the following formula (based on sex, weight, and age) can approximate CrCl. Serum creatinine should represent a steady state of renal function.

In patients with severe renal failure (CrCl < 10 mL/min/1.73 m2) and those supported by hemodialysis, a usual dose of 500 mg, 1 g, or 2 g, is given initially.

The maintenance dose is one fourth of the usual initial dose given at a usual fixed interval of 6, 8, or 12 hours.

For serious or life-threatening infections, supplement the maintenance doses with one eighth of the initial dose after each hemodialysis session.

Elderly persons may have diminished renal function. Renal status is a major determinant of dosage in these patients. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, obtain estimates of the CrCl, and make appropriate dosage modifications. Data are insufficient regarding intramuscular (IM) administration to pediatric patients or dosing in pediatric patients with renal impairment. Aztreonam is administered IV only to pediatric patients with normal renal function.

Cefepime is the best beta-lactam for IM administration. This agent is a fourth-generation cephalosporin that has gram-negative coverage comparable to ceftazidime but with better gram-positive coverage (comparable to ceftriaxone). Cefepime is a zwitter ion, so it rapidly penetrates gram-negative cells. However, this agent has a poor capacity to cross the blood-brain barrier, which precludes its use for the treatment of meningitis.

Cefotaxime is a third-generation cephalosporin with broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. It acts by arresting bacterial cell wall synthesis by binding to one or more penicillin-binding proteins, which, in turn, inhibits bacterial growth. Cefotaxime is used for septicemia and treatment of gynecologic infections caused by susceptible organisms, but it has a lower efficacy against gram-positive organisms.

Ciprofloxacin is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for the replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms but no activity against anaerobes. Continue ciprofloxacin treatment for at least 2 days (7-14 d typical) after the patient's signs and symptoms have disappeared.

Clindamycin is a lincosamide semisynthetic antibiotic produced by 7(S)-chloro-substitution of 7(R)-hydroxyl group of the parent compound lincomycin. This agent inhibits bacterial growth, possibly by blocking the dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Clindamycin widely distributes in the body without penetration of the central nervous system (CNS). It is protein bound and excreted by liver and kidneys.

Clindamycin is available in parenteral (ie, clindamycin phosphate) and oral form (ie, clindamycin hydrochloride). Oral clindamycin is absorbed rapidly and almost completely and is not appreciably altered by presence of food in stomach. Appropriate serum levels are reached and sustained for at least 6 hours following the oral dose. No significant levels are attained in the cerebrospinal fluid (CSF). Clindamycin is also effective against aerobic and anaerobic streptococci (except enterococci).

Doxycycline is an alternative agent for patients who cannot tolerate macrolides or penicillins. This agent is a broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. Doxycycline is almost completely absorbed, concentrates in the bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations.

This agent is a carbapenem antibiotic that has bactericidal activity resulting from inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin-binding proteins. Ertapenem is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, cephalosporinases, and extended-spectrum beta-lactamases. It is hydrolyzed by metallo-beta-lactamases.

Linezolid is used as an alternative drug in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci. It is also effective against MRSA and penicillin-susceptible S pneumoniae infections.

This agent is an oxazolidinone antibiotic that prevents formation of the functional 70S initiation complex, which is essential for bacterial translation process. Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci.

The FDA warns against the concurrent use of linezolid with serotonergic psychiatric drugs, unless indicated for life-threatening or urgent conditions. Linezolid may increase serotonin CNS levels as a result of MAO-A inhibition, increasing the risk of serotonin syndrome.
[72]

Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. This drug is used in combination with both an agent against gram-positive organisms and one that covers anaerobes.

Note that gentamicin is not the drug of choice. Consider using this drug if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. The dosing regimens are numerous. Adjust the dose based on CrCl and changes in volume of distribution. Gentamicin may be administered IV/IM.

Amoxicillin and clavulanate is an alternative agent for patients who are allergic or intolerant to macrolides. Amoxicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. The addition of clavulanate inhibits beta-lactamase producing bacteria.

This drug combination is usually well tolerated and provides good coverage to most infectious agents. However, it is not effective against Mycoplasma and Legionella species. The half-life of the oral dosage form is 1-1.3 hours, and it has good tissue penetration but does not enter the cerebrospinal fluid.

For children older than 3 months, base the dosing protocol on the amoxicillin content. Due to different amoxicillin/clavulanic acid ratios in the 250-mg tablet (250/125) vs 250 mg chewable tablet (250/62.5), do not use the 250-mg tablet until the child weighs >40 kg.

This drug is a combination of beta-lactamase inhibitor with ampicillin that is used as an alternative to amoxicillin when the patient unable to take oral medication. Ampicillin and sulbactam covers skin flora, enteric flora, and anaerobes, but it is not ideal for nosocomial pathogens. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms.

Ceftazidime is a third-generation cephalosporin with broad-spectrum, gram-negative activity, including Pseudomonas; low efficacy against gram-positive organisms; and high efficacy against resistant organisms. This agent arrests bacterial growth by binding to one or more penicillin-binding proteins, which, in turn, inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell wall synthesis, thus inhibiting cell wall biosynthesis.

The condition of the patient, severity of infection, and susceptibility of the microorganism should determine the proper dose and route of administration.

Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity; low efficacy against gram-positive organisms; and high efficacy against resistant organisms. It is considered the drug of choice for parenteral agents in community-acquired pneumonia. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin binding proteins. This agent exerts its antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of the bacterial cell wall. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes while the cell wall assembly is arrested.

Ceftriaxone is highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase, and of gram-negative and gram-positive bacteria. Approximately 33-67% of the dose excreted unchanged in urine, and the remainder is secreted in bile and, ultimately, in feces as microbiologically inactive compounds. This agent reversibly binds to human plasma proteins, and binding has been reported to decrease from 95% bound at plasma concentrations of less than 25 mcg/mL to 85% bound at 300 mcg/mL.

Amoxicillin is a penicillin derivative of ampicillin with a similar antibacterial spectrum, namely certain gram-positive and gram-negative organisms. This agent has superior bioavailability and stability to gastric acid and has a broader spectrum of activity than penicillin. However, amoxicillin is somewhat less active than penicillin against S pneumococcus. Penicillin-resistant strains are also resistant to amoxicillin, but higher doses may be effective. Amoxicillin is more effective against gram-negative organisms (eg, N meningitidis, H influenzae) than penicillin.

This agent interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Imipenem and cilastatin is a carbapenem antibiotic used for treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to the potential for toxicity. Use this agent with caution in the presence of renal insufficiency (adjust the dose), a history of seizures, and hypersensitivity to penicillins, cephalosporins, or other beta-lactam antibiotics. Avoid administering to children younger than 12 years with CNS infections.

Levofloxacin is rapidly becoming a popular choice in pneumonia; this agent is a fluoroquinolone used to treat CAP caused by S aureus, S pneumoniae (including penicillin-resistant strains), H influenzae, H parainfluenzae, Klebsiella pneumoniae, M catarrhalis, C pneumoniae, Legionella pneumophila, or M pneumoniae. Fluoroquinolones should be used empirically in patients likely to develop exacerbation due to resistant organisms to other antibiotics.

Levofloxacin is the L stereoisomer of the D/L parent compound ofloxacin, the D form being inactive. It has good monotherapy with extended coverage against Pseudomonas species and excellent activity against pneumococcus. Levofloxacin acts by inhibition of DNA gyrase activity. The oral form has a bioavailability that is reportedly 99%.

The 750-mg dose is as well tolerated as the 500-mg dose, and it is more effective. Other fluoroquinolones with activity against S pneumoniae may be useful and include moxifloxacin, gatifloxacin, and gemifloxacin

Clarithromycin is another initial drug of choice that is used in otherwise uncomplicated pneumonia. It is used to treat CAP caused by H influenzae, M pneumoniae, S pneumoniae, M catarrhalis, H parainfluenzae, or C pneumoniae (TWAR strain). Clarithromycin appears to cause more GI symptoms (eg, gastric upset, metallic taste) than azithromycin.

This agent is a semisynthetic macrolide antibiotic that reversibly binds to the P site of the 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.

Erythromycin covers most potential etiologic agents, including Mycoplasma species. The oral regimen may be insufficient to adequately treat Legionella species, and this agent is less active against H influenzae. Although the standard course of treatment is 10 days, treatment until the patient has been afebrile for 3-5 days seems a more rational approach. Erythromycin therapy may result in GI upset, causing some clinicians to prescribe an alternative macrolide or change to a tid dosing.

Erythromycin is a macrolide that inhibits bacterial growth possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Vancomycin is classified as a glycopeptide agent that has excellent gram-positive coverage, including methicillin-resistant S aureus (MRSA). To avoid toxicity, current recommendations indicate to assay vancomycin trough levels after the third dose drawn 0.5 hour before the next dosing. Use CrCl to adjust the dose in patients diagnosed with renal impairment.

Telavancin is a lipoglycopeptide antibacterial that is a synthetic derivative of vancomycin. It is indicated for treatment of adults with hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Staphylococcus aureus, including methicillin-susceptible and resistant isolates. This agent is reserved for use when alternative treatments are not suitable.

Meropenem is indicated for community-acquired pneumonia, including multi–drug-resistant S pneumoniae. This agent is a bactericidal broad-spectrum carbapenem antibiotic that inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription, and inhibits cell wall synthesis.

Meropenem is effective against most gram-positive and gram-negative bacteria and has slightly increased activity against gram-negatives and slightly decreased activity against staphylococci and streptococci compared with imipenem.

Moxifloxacin is a fluoroquinolone that inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Use caution in prolonged therapy, and perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic). Note that superinfections may occur with prolonged or repeated antibiotic therapy, and fluoroquinolones have induced seizures in patients with CNS disorders as well as caused tendinitis or tendon rupture.

Ampicillin is a broad-spectrum penicillin that interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. This agent is used as an alternative drug to amoxicillin when the patient is unable to take oral medication.

The piperacillin and tazobactam sodium combination is an antipseudomonal penicillin plus beta-lactamase inhibitor. This agent inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.

Perform CBC counts before the initiation of therapy and at least weekly during therapy. In addition, monitor for liver function abnormalities by measuring AST and ALT levels during therapy, and perform urinalysis and BUN and creatinine determinations during therapy. Adjust the dose if laboratory values become elevated, and monitor blood levels to avoid possible neurotoxic reactions.

Ceftaroline is a fifth-generation cephalosporin indicated for community-acquired bacterial pneumonia and for acute bacterial skin and skin structure infections, including methicillin-resistant Staphylococcus aureus (MRSA). This agent is a beta-lactam cephalosporin with activity against aerobic and anaerobic gram-positive and aerobic gram-negative bacteria. It demonstrates activity in vivo against resistant MRSA strains and activity in vitro against vancomycin-resistant and linezolid-resistant S aureus

Cefprozil binds to one or more of the penicillin-binding proteins, inhibiting cell wall synthesis and resulting in bactericidal activity. Use this agent with caution in patients with renal impairment (coadministration with furosemide and aminoglycosides increases nephrotoxic effects). Probenecid coadministration also increases the effect of cefprozil

Hydrocortisone is the drug of choice because of its mineralocorticoid activity and glucocorticoid effects.

Previous

Next:

Vaccines

Class Summary

Pneumococcal vaccines are recommended as part of routine prophylaxis in young children (aged < 5 y) and adults aged 65 y or older. These vaccines are also recommended for individuals who are immunocompromised (eg, HIV, cancer, renal disease), or have functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants.

Centers for Disease Control and Prevention. H1N1 Flu: Updated CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States April 2009 - April 10, 2010. Available at http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm. Accessed: June 1, 2010.